The overall goal of this project is to develop a safe, non-invasive non-ablative focused ultrasound therapy (NAFU) which can be used for the treatment of primary carcinoma and prevention of metastases by increasing tumor immunogenicity. NAFU treatment be used as an adjuvant therapy with current therapies, such as chemotherapy, immunotherapy, surgery, radiotherapy, and HIFU. This proposal will establish the role of NAFU in generating systemic anti-tumor immunity and define specific protocols for inducing ER stress and augmenting tumor immunomodulatory markers, such as heat shock protein 70, calreticulin, ATP and HMGB1. NAFU will be combined with two different novel immunotherapies: a dendritic cell-based vaccine and a Listeria-based prostate cancer vaccine. Preliminary data indicates that NAFU-treatment increases cell surface immunomodulation, which when cultured with dendritic cells ex vivo will result in an enhanced autologous vaccine. Additionally, preliminary studies demonstrate that NAFU-treatment of a live, attenuated Listeria-based vaccine for prostate cancer enhances phagocytosis of the bacteria, resulting in a more robust immune response and control of tumor burden. Together these projects will solidify non-ablative focused ultrasound as an effective cancer treatment option which will induce systemic anti-tumor immunity, treat primary tumors, and reduce metastases.